Small alarmones (p)ppGpp regulate virulence associated traits and pathogenesis ofSalmonella entericaserovar Typhi

Abstract

How Salmonella enterica serovar Typhi (S. Typhi), an important human pathogen, survives the stressful microenvironments inside the gastrointestinal tract and within macrophages remains poorly understood. We report here that S. Typhi has a bonafide stringent response (SR) system, which is mediated by (p)ppGpp and regulates multiple virulence-associated traits and the pathogenicity of the S. Typhi Ty2 strain. In an iron overload mouse model of S. Typhi infection, the (p)ppGpp 0 (Ty2ΔRelAΔSpoT) strain showed minimal systemic spread and no mortality, as opposed to 100% death of the mice challenged with the isogenic wild-type strain. Ty2ΔRelAΔSpoT had markedly elongated morphology with incomplete septa formation and demonstrated severely attenuated motility and chemotaxis due to the loss of flagella. Absence of the Vi-polysaccharide capsule rendered the mutant strain highly susceptible to complement-mediated lysis. The phenotypes of Ty2ΔRelAΔSpoT was contributed by transcriptional repression of several genes, including fliC, tviA, and ftsZ, as found by reverse transcriptase quantitative polymerase chain reaction and gene complementation studies. Finally, Ty2ΔRelAΔSpoT had markedly reduced invasion into intestinal epithelial cells and significantly attenuated survival within macrophages.To the best of our knowledge, this was the first study that addressed SR in S. Typhi and showed that (p)ppGpp was essential for optimal pathogenic fitness of the organism.

Emerging and divergent roles of pyrophosphorylated nucleotides in bacterial physiology and pathogenesis

“…In S . Typhimurium, it is well established that (p)ppGpp regulates genes required for the invasion of intestinal epithelial cells and intracellular survival ( Fig 3A ) [ 34 , 42 , 77 – 81 ]. Complementing these findings, recent work shows that the exposure of S .…”

Survival of the Fittest: The Relationship of (p)ppGpp With Bacterial Virulence

“…Salmonella enterica is responsible for a variety of human infections ranging from gastroenteritis to typhoid fever. Early studies with (p)ppGpp 0 strains (Δ relA Δ spoT ) of S. enterica serovar Typhimurium, Typhi, and Gallinarum clearly demonstrated the essentiality of (p)ppGpp to Salmonella pathogenesis ( Pizarro-Cerda and Tedin, 2004 ; Jeong et al, 2008 ; Park et al, 2010 ; Dasgupta et al, 2019 ). Interestingly, (p)ppGpp was found to regulate the expression of Salmonella pathogenicity islands 1 (SPI-1) and 2 (SPI-2), which are required for Salmonella virulence ( Pizarro-Cerda and Tedin, 2004 ; Song et al, 2004 ).…”

Complement evasion mechanisms of the systemic pathogens Yersiniae and Salmonellae

“…Decreased C3 fixation due to Vi capsule has more recently been shown to specifically prevent CR3-mediated adherence and invasion of human macrophage-like cells, as well as prevent clearance of S. Typhi from the liver and spleen of mice in a short-term infection model [162]. Additionally, absence of Vi capsule caused by mutation of genes involved in the stringent response system led to susceptibility to complement-mediated lysis [163].…”